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Innate immunity: sensing and signalling
Eicke Latz and Katherine A. Fitzger ald
In response to microbial products, distinct families of pattern-r ecognition receptors
initiate intracellular signalling events that lead to complex immune responses designed
to eliminate invading pathogens. These include receptors that recognize conserved
molecular patterns derived from bacteria, viruses, protozoa and fungi (the TLRs), receptors
that sense fungi (the CLRs), and receptors in the cytosol that sense viral nucleic acids (the
RLRs and DAI) or bacterial products (the NLRs). The NLRs also sense endogenous products
released by dying cells. These receptors, with the exception of the NALP proteins of the
NLR family, recruit adaptor molecules, which in turn create multi-pr otein platforms to
which additional kinases, transcription factors and possibly other molecules are recruited.
These events ultimately lead to the expression of genes that encode key factors that
regulate the immune response. Some of these factors require additional processing, which
is carried out by members of the NLR family. Given the rapidity at which such interactions
have been described, here, we attempt to summarize our curr ent understanding of these
events in an effort to provide a framework for future studies.
Innate immune receptors
LBP
LPS
CD14
TLR1, TLR2,
TLR6
TLR4
TLR5
TLR11
Dectin-1
LRR
MD2
Fc RIII
(CD16)
MAIRI
TREM1
Dectin-2
FcR
DAP12
TIR domain
Cytoplasm
Mitochondrion
TRIM25
MDA5
TRIF
MyD88
TRAM
MAL
ITAM
IPS1
RIG-I
DAI
IL-1
Pro-caspase-1
TANK NAP1
SINTBAD
p38
JNK
P
ATF2
P
JUN
Pro-caspase-8
P
P
IRF3
P
P
IRF7 IRF3
P
P
P
P
IRF3 IRF3
P
P
TAK1
p38
JNK
MALT1
TAK1
IRAK1
IRAK1
TRAF6
TRAF6
TRAF3 TRAF6
P
ATF2
P
JUN
P P
IRF5
P P
IRF5
IRF7
IRF1
P
P
IRF5
IRF7
P
P
IRF1
TAB2
TAB3
Pro-IL-1
IRAK1
IRF5
CARD9
BCL-10
CARD9
Active
caspase-1
IKK
IKK IKK
MAPKK
P I B
p50 p65
p50 p65
TAB2
TAB3
CARD9
Proteolytic
cleavage
TRAF6
IKK
IKK IKK
IRF7
NOD
RIP2
Proteolytic
cleavage
IRAK2,
IRAK4
TAK1
Caspase-8
TBK1
IKK IKK
MAPKK
NALP3
inflammasome
RIP1
FADD
P
P
ASC
Endosome
TRAF3
P
P
NOD1 or
NOD2
TLR7,
TLR8,
TLR9
TLR3
P
P
P
NALP3
IPS1
Ub
P SYK
P
P
P NFAT
P I B
p50 p65
NFAT
p50 p65
MAPKK
p38
JNK
P
ATF2
P
JUN
P
P
NF- B
Nucleus
Type I IFNs
MedImmune
MedImmune strives to provide better medicines to patients, new
medical options for physicians and rewarding careers to employees.
Dedicated to advancing science and medicine to help people live better
lives, the company is focused on the areas of infectious disease, cancer
and inflammatory disease. The company’s marketed products include
Synagis® (palivizumab) and FluMist® (Influenza Virus Vaccine Live,
Intranasal), with additional products in clinical testing. MedImmune has
multiple programs underway to develop potential treatments targeted
at a variety of respiratory and inflammatory diseases such as asthma,
lupus and rheumatoid arthritis. With approximately 3,000 employees
worldwide and headquarters in Maryland, USA, MedImmune is wholly
owned by AstraZeneca plc (LSE: AZN.L, NYSE: AZN). For more
information, visit the company’s website at www.medimmune.com.
Pro-inflammatory
cytokines
including pro-IL-1
Abbreviations
AraLAM, non-mannose-capped lipoarrabinomannan; ASC, apoptosisassociated speck-like protein containing a CARD; ATF2, activating
transcription factor 2; BCL-10, B-cell lymphoma 10; BIR, baculoviral IAP
repeat; CARD, caspase-recruitment domain; CLR, C-type lectin receptor;
CPPD, calcium pyrophosphate dihydrate; DAI, DNA-dependent activator of
IRFs; DC, dendritic cell; dsDNA, double-stranded DNA; FADD, FAS-associated
via death domain; Fc R, Fc receptor for IgG; FcR, Fc receptor; FIIND,
function-to-find domain; GIPL, glycoinositolphospholipid; I B, inhibitor of
NF- B; iE-DAP, - -glutamyl-meso-diaminopimelic acid; IFN, interferon;
IKK, I B kinase; IL, interleukin; IPAF, ICE-protease activating factor; IPS1,
IFNB-promoter stimulator 1; IRAK, IL-1 receptor-associated kinase; IRF, IFNregulatory factor; ITAM, immunoreceptor tyrosine-based activation motif;
JNK, JUN N-terminal kinase; LBP, LPS-binding protein; LPS, lipopolysaccharide;
LRR, leucine-rich repeat; LTA, lipoteichoic acid; MAL, MyD88-adaptor-like
protein; MALT1, mucosa-associated-lymphoid-tissue lymphoma-translocation
gene 1; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase;
Type I IFNs
MDA5, melanoma differentiation-associated gene 5; MDP, muramyl dipeptide;
MMTV, mouse mammary tumour virus; MSU, monosodium urate; MyD88,
myeloid differentiation primary-response gene 88; NACHT, domain present
in NAIP, CIITA, HET-E and TP1; NAIP, neuronal apoptosis inhibitory protein;
NALP, NACHT-, LRR- and PYD-domain-containing protein; NAP1; NAKassociated protein 1; NFAT, nuclear factor of activated T cells; NF- B, nuclear
factor- B; NLR, nucleotide-binding domain LRR-containing family; NOD,
nucleotide-binding oligomerization domain; Pam2CSK4, Pam2Cys-Ser-LysLys-Lys-Lys; PGN, peptidoglycan; PI5K, phosphoinositide 5-kinase; PKC,
protein kinase C; polyI:C, polyinosinic–polycytidylic acid; PtdIns(4,5)P2,
phosphatidylinositol-4,5-bisphosphate; PYD, pyrin domain; RIG-I, retinoicacid-inducible gene I; RIP, receptor-interacting protein; RLH, RIG-I-like RNA
helicases; RLR, RIG-I-like receptor; RSV, respiratory syncytial virus;
SINTBAD, similar to NAP1 TBK1 adaptor; ssRNA, single-stranded RNA;
SYK, spleen tyrosine kinase; TAB, TAK1-binding protein 1; TAK, TGF activated kinase; TANK, TRAF-family-member-associated NF- B activator;
TBK, TANK-binding kinase; TIR, Toll/IL-1 receptor; TLR, Toll-like receptor;
Pro-inflammatory
cytokines
TNP, trinitrophenyl; TRAF, TNF-receptor-associated factor; TRAM, TRIFrelated adaptor molecule; TREM, triggering receptor expressed on myeloid
cells; TRIF, TIR-domain-containing adaptor protein inducing IFN ; TRIM25,
tripartite-motif-containing 25; Ub, ubiquitin.
Affiliations
Eicke Latz and Katherine Fitzgerald are at the Division of Infectious
Diseases & Immunology, University of Massachusetts Medical School,
364 Plantation Street, Worcester, Massachusetts 01605, USA.
e-mails: eicke.latz@ umassmed.edu; kate.fitzgerald@ umassmed.edu
Edited by Olive Leavy; copy edited by Marta Tufet;
designed by Simon Bradbrook.
2008 Nature Publishing Group.
http://www.nature.com/nri/poster/innate
RLRs and DAI. The cytoplasm contains proteins that sense DNA or RNA
derived from invading viruses. RNA is recognized by the RLR family of
proteins, which consists of at least two members, RIG-I and MDA5. LGP2,
a related family member (not depicted), may act as a negative regulator
of these receptors by sequestering RNA. RIG-I recognizes 5 -triphosphate
RNAs, whereas MDA5 is thought to sense dsRNA. The E3-ubiquitin ligase
TRIM25 induces ubiquitylation of RIG-I, which is essential for RIG-I
function.
The RLRs contain CARD domains that recruit IPS1 (also known as
CARDIF, MAVS or VISA), which is an adaptor molecule that is tethered
to the mitochondria. IPS1 associates with the E3-ubiquitin ligase TRAF3
and activates the IKK-related kinases TBK1 and IKK , which
phosphorylate and activate IRF3 and IRF7, the key regulators of type I
IFN gene transcription in most cell types. IKK , TANK, NAP1 and
SINTBAD form a complex with these kinases. IPS1 also induces NF- B
activation through FADD and caspase-8 and/or caspase-10, and
activates the MAPKs p38 and JNK. Cells also contain DNA sensors in the
cytoplasm. One such protein DAI (also known as ZBP1) binds dsDNA
and activates IRF3 through TBK1.
TLRs. The TLRs are type I transmembrane receptors found on the plasma
membrane or in endosomal compartments. Upon ligand binding, they
recruit adaptor molecules through TIR–TIR interactions. Signalling by
TLR5, TLR7, TLR8, TLR9 and TLR11 relies solely on MyD88, whereas TLR1,
TLR2 and TLR6 also recruit MAL (also known as TIRAP). TLR3 signals
independently of MyD88 and MAL through TRIF (also known as TICAM1).
TLR4 uses MAL and TRAM to recruit MyD88 and TRIF. MAL is targeted to
the plasma membrane through a PtdIns(4,5)P2-binding domain, whereas
TRAM is anchored though myristoylation at its N-terminus. PKC
regulates TRAM function (see TLR4 inset). Signalling through these
adaptorsNLRs
leads to either NF- B or IRF3 activation.
NALP1
IRAK2 and IRAK4,
activated by MyD88, are crucial for NF- B activation.
CARD
They enable
the recruitment
and activation of TRAF6, which activates
Caspase-5
TAK1 through
K63-linked polyubiquitylation. TAK1 in turn activates the
FIIND
NALP3 IPAF
IKK complex, which phosphorylates
I B andNAIP
targets it for ubiquitylation
LRR degradation by the proteasome. NF- B is then released,
and subsequent
translocates to the nucleus and regulates the expression of its target
genes, which
include pro-inflammatory cytokines. TAK1 also controls
NAD
activation of the MAPK pathway. TRIF activates NF- B through RIP1,
NACHT
and activates
IRF3 through TRAF3, which associates with TBK1 and IKK
leading to type I IFNASC
gene transcription.
PYD
TLR7, TLR8 and TLR9 activate NF- B as BIR
well as IRF1, IRF5 and IRF7
through MyD88. In plasmacytoid DCs IRF7 is a crucial factor for IFN
production, whereas IRF1 and IRF5 control the IFN response in
conventional DCs.
IKK is thought to have a role in IRF7 activation
Caspase-1
in plasmacytoid DCs. IRF5 is activated downstream of most, if not all,
the TLRs through MyD88 and IRAK1 and in this case regulates proinflammatory cytokine production.
NLRs. This large receptor family of more than 20 proteins in humans
contains NOD1, NOD2, NALPs, IPAF and NAIP. The NOD proteins
recognize different moieties of bacterial PGN and activate NF- B through
RIP2 (also known as RICK) and MAPK through CARD9. NALPs and IPAF
form multimolecular complexes termed ‘inflammasomes’ following their
activation. NALP3 recruits the adaptor molecule ASC that in turn recruits
pro-caspase-1, which is activated by autocatalytic cleavage. Cleaved
caspase-1 catalyses proteolytic processing of pro-IL-1 (and pro-IL-18,
not shown) into the active cytokines that are then released.
CLRs. Activation of members of the CLR protein family can induce the
production of pro-inflammatory cytokines, promote phagocytosis and
elicit a respiratory burst. SYK interacts with phosphotyrosines within
ITAMs in dectin-1 or in associated signalling chains to initiate a CARD9dependent activation of the BCL-10–MALT1 complex. This complex can
subsequently initiate NF- B signalling through the activation of the IKK
complex. TREM proteins also associate with adaptor proteins that
contain ITAMs to initiate CARD9 signalling. The CLRs trigger MAPK
activation and in the case of dectin-1 activate NFAT in myeloid cells to
regulate pro-inflammatory cytokine production.